How the genetic code was cracked

some possible 3-letter codes
The structure of DNA, solved in 1953, set off a race to crack the genetic code. How do sequences of 4 nucleotides code for sequences of 20 amino acids? This coding problem lies at the heart of molecular biology. Physicist George Gamow of Big Bang fame contributed the first guess: Spaces between neighboring nucleotides might fit individual amino acids, directly templating protein assembly on the DNA. In Gamow's solution, each nucleotide must contribute to defining two amino acids–an overlapping code. The numerology looked good (there were exactly 20 possible combinations), but Gamow's solution turned out to be wrong: In 1957, Sydney Brenner devised a simple test that disproved this and all overlapping triplet codes. The true code was soon cracked based on beautiful frameshift experiments by Crick et al., and by analysis of proteins synthesized from artificial RNAs.
Supplements: Gamow's guess, Brenner disproves Gamow and all overlapping triplet codes, the decisive artificial RNA experiments

Sound as sight: the discovery of bat echolocation

The question of how bats navigate in almost complete darkness has fascinated natural scientists since the 1700's. The famous anatomist Cuvier suggested that the wing membranes contained tactile sensors that allowed bats to navigate around objects. Others discovered that the ears seemed to be the most important organ (Spallanzani, Jurine and Hahn), but since bats rarely made sounds audible to humans, no one could discern how bats followed their ears. This conundrum was finally solved by the team of zoologist David Griffin and neuroscientist Robert Galambos in 1941, as America was entering World War II. By covering the eyes, ears, and mouths of bats, they determined that both the mouth and the ears were necessary for successful flight. They continued their studies with sound capture and brain monitoring technology, and determined that bats navigate by bouncing high-pitched calls off their surroundings and analyzing the echoes. This discovery tied in well with the sonar and radar biased thinking of the War, and eventually led to the ill-fated bat bomb project which was scrapped in favor of the atomic bomb.
Image credit 

What triggers RNAi?

The discovery of RNA interference revolutionized the way we determine the role of a gene.  The gene silencing phenomenon has been shown since the early 1990s when introduction of sense or anti-sense RNA could cause a reduction of endogenous messenger RNA.  In 1998, Fire and Mello provided an explanation for the previously reported silencing effect.  Their seminal paper shows that it was not ssRNA that silenced the endogenous RNA, but in fact dsRNA.  So how did ssRNA cause silencing in previous reports?  It is believed that their ssRNA preparations were contaminated with complementary RNA!  Fire and Mello overcame this by extensively purifying their RNA.  Indeed,  they showed that ssRNA was consistently found to be 10 to 100 fold less effective than double stranded.  To this day biologists continue to make great strides in understanding the roles of genes due to this discovery.
Nobel prize article and image credit 

How the widowbird got its absurdly long tail

Wikimedia Commons
One glaring difficulty for early evolutionary biologists was the evolution of exaggerated male secondary sexual traits, which should hinder the survival of males.  Darwin was the first to suggest that sexual selection favoring an exaggerated trait could 'override' natural selection opposing the same trait, as long as the reproductive benefits outweighed the survival costs associated with it.  During the modern synthesis, Ron Fisher proposed a mechanism of ornament evolution, wherein female preferences for an initially advantageous male trait drive that trait to an extreme value such that it no longer confers a survival advantage.  Despite these theoretical advances, little empirical evidence of sexual selection on elaborate traits existed even in the early '80s.  Anderrson's work on Long-tailed Widowbirds provided the first experimental evidence of female preference for a male ornament.  This beautifully designed manipulation study was able to control for the confounding influence of variation in male territory quality, the experimental manipulation, and male behavior.
And a later paper summarizing subsequent work on widowbirds

Discovery of the first molecular basis for a disease

It is obvious now that defects in proteins, normally because of mutations in the DNA, cause many diseases, but it was not so evident in 1949.

Linus Pauling and his collaborators knew that only deoxygenated blood contains the sickle shaped erythrocytes (see picture) characteristic of sickle cell anemia, which lead them to the hypothesis that hemoglobin was involved in this problem.

They showed that hemoglobin from patients suffering from sickle cell anemia is different (has different electrophoretic mobility) to the “healthy hemoglobin”. In addition, they found that people with sicklemia, a less severe version of the disease, contain both forms of the protein. This was proof of a change in a protein causing a disease!
More important that the actual experiment, are the conclusions derived of it. Not only this was the beginning of “molecular medicine”, but the genetic discussion in the paper is groundbreaking.
Image credit
More about it

Evolution in action: Darwin's finches
Since the publication of Darwin's "On the Origin of Species", we have had an outline for how evolution can occur by natural selection. There must be variation in a trait between individuals, that variation must be heritable, and more individuals must be produced than can survive and reproduce.  Natural selection can then act on that variation, leading to changes in population frequencies of the trait value. Theoretically, this scheme makes sense, but empirically it is difficult to observe, since evolution acts over large time scales.  Enter Peter and B. Rosemary Grant. The Grants went back to Darwin's birds, the Galapagos finches, to try to peek at evolution in action. Beginning in 1976, they and their students spent months of every year in the Galapagos, measuring everything they could about the finches and their habitat. Then, between 1982 and 1983, the most extreme El Nino event in 400 years occurred, and the Grants finally got their chance. Their 1993 paper reports their findings.
Additional: "Ecology and the Origin of Species"

How does the environment affect evolution? Waddington's example of genetic assimilation

Conrad Waddington, throughout his long and varied career as a developmental biologist, was foundational to several aspects of modern evolutionary theory, such as epigenetics, developmental canalization, and genetic assimilation. One of the great puzzles of evolution is how organisms can become so specifically and heritably adapted to their environment. Random genetic mutations can sometimes serve as the sole explanation, but not always. Through several rather cleverly simple experiments, Waddington demonstrated that phenotypes elicited by a specific environmental cue (such as heat shock or ether treatment) could be "assimilated" into the genotype. This means that the phenotype could eventually be expressed even if the corresponding cue was absent. He argued that this phenomena, which he witnessed in Drosophila in less than 30 generations, could play a powerful and vital role in evolution.
Background paper: Genetic assimilation of cross-veinless phenotype (1953)

Barbara McClintock discovers "jumping genes"

Transposable elements (TE) are DNA sequences that “jump” from one location in the genome to another.  McClintock’s work not only showed that sequences can move, but also that this movement across the genome can create and reverse mutations as well as alter genome size, all during various stages of cell development.  McClintock conducted standard genetic self-breeding experiments causing broken chromosomes and noted unusual color patterns in the offspring, to understand the cause of this variety she compared the chromosomes of each generation with that of the parent and found that certain sections of the chromosomes had switched their position.  At first her discovery was met with skepticism because it went directly against the popular theory at the time that genes were fixed in their chromosomal position but McClintock’s work was rediscovered through work in bacteria a decade later and earned her a Nobel Prize in 1983.
Supplementary paper:  Junk DNA as an evolutionary force

How DNA replicates itself

After the structure of DNA was elucidated by Watson and Crick, one of the next burning questions was how is it replicated? The aforementioned individuals contributed the first hypothesis: that DNA replication is semi-conservative. That is, each strand of DNA serves as a template for a newly synthesized strand. A second was the conservative hypothesis, that the entire DNA molecule serves as a template for a new DNA molecule. And finally, the dispersive hypothesis proposed by Max Delbrück argues that a mechanism exists that would break the strand every so often and attaches a new strand to the old one. To test this, Matthew Meselson and Franklin Stahl, in an incredibly elegant experiment published in 1958, grew E. coli first with 15N then with 14N and allowed to divide. They periodically extracted the DNA and centrifuged the DNA in a cesium chloride density gradient. The results were obvious. Through cell division, half of the DNA was replaced with new DNA, favoring the Watson and Crick hypothesis that DNA replication is semi-conservative.

Lenski replays evolution in long term E. coli populations

Richard Lenski's longterm evolution experiments on E. coli are a hallmark example of evolutionary biology. Lenski and colleagues have maintained 12 parallel lines of E. coli for 50,000 generations now. Initially, these E. coli populations were founded by clones, and over decades, researchers have watched evolutionary dynamics on a scale observable in real time.

This particular paper, published in 2008, describes the acquisition of a novel phenotype - the ability to metabolize citrate in addition to glucose as an energy source.

Lenski's experiments on the evolution of citrate use are particularly elegant for the following reason: The lab maintains frozen samples of the E. coli populations at time points throughout the history of the populations. These samples are not growing (and therefore not mutating) while frozen, but can be pulled from the freezer and reconstituted. This allowed researchers to go back to previous timepoints in the evolution of this phenotype and "replay evolution" to see if the same phenotypes arise again ...

The Discovery of Passive Immunity

After vaccinations were shown to be successful at protecting individuals against pathogens, researchers next wanted to know how it worked. To address this, immunologists Emil Behring and Shibasaburo Kitasato teamed up to work together in Germany. They injected serum from immunized rabbits into the abdominal cavity of six mice. After twenty-four hours they infected the treated and untreated mice with virulent tetanus bacteria. All of the control mice died, but the treated mice survived and showed no sign of infection. This important discovery showed that the substances that impart the protection appear in serum following immunization and that immunity can be passively acquired. Behring eventually received the first Nobel Prize in Physiology or Medicine for this work. 

On spontaneous generation and the lack thereof (discussed by the group on 9/4/13)

Pasteur: The Chemist Who Transformed Medicine
Collection of the University of Michigan Health System
Commissioned by Parke-Davis & Co. in the 1950s as
part of a 45 oil painting series titles 'A History
of Medicine in Pictures' by Robert Thom.

Spontaneous generation, a widely held belief first described in the 5th century BCE, is eloquently explained by Aristotle as organisms  "not derived from living parentage, but [that are] generated spontaneously: some out of dew falling on leaves, ordinarily in spring-time, but not seldom in winter…" was decidedly disproved by recent experiments of Louis Pasteur, a modern scientist of the 19th century. In a series of articles published in the 1860s, the author describes the introduction of "amianthus charged with atmospheric dust" to boiled milk or urine resulting in the growth of bacteria, including "very minute Vibriones, and Monads" leading to putrefaction. The boiled liquid when untouched remained unchanged, suggesting a substance contained on or within the dust promoted the growth of microorganisms. This simple set of experiments led to the confirmation of biogenesis (life from life) and the subsequent discovery that certain microorganisms cause disease (germ theory).
Note: Here is a free version of the text of the third paper. The Aristotle reading is quite long, so you might want to read just the sections that discuss spontaneous generation, excerpted here. Also, you might be interested to learn about some related, beautiful and well-controlled experiments reported in 1688 by Francesco Redi. -Bob

Berche, P. (2012), Louis Pasteur, from crystals of life to vaccination. Clinical Microbiology and Infection, 18: 1–6.

How do growing nerve cells find their targets?

Rita Levi-Montalcini (photo credit)
In 1949, Rita Levi-Montalcini noticed something unexpected. Her colleague Elmer Bueker had found that nerves would invade tumors that he had implanted into chick embryos. What attracted the nerves to tumors? Indeed, how did nerves ever find their normal targets? What Levi-Montalcini noticed: the nerves would invade not just the tumors, but also the tissues near the tumors–suggesting that the tumors might have been releasing a diffusible nerve growth factor, a postulated substance that could guide either nerve differentiation, growth or survival. Levi-Montalcini proved the existence of a nerve growth factor by culturing just tumors and ganglia in the same dish, finding that the nerves from the ganglia would connect to tumors even in vitro. Later, she purified the key protein, now called Nerve Growth Factor (NGF). NGF told us that the way nerves find their targets is unexpectedly adaptive–nerves grow just about everywhere, and they die off if they fail to find targets. 
A short review: Aloe, L. (2004) Rita Levi-Montalcini: the discovery of nerve growth factor and modern neurobiology. Trends Cell Biol 14:395-9. 

Some amazing historical background: An excerpt about her pre-NGF work done in makeshift home labs she set up hiding out in the hills during WWII, from her autobiography, In Praise of Imperfection. Open the excerpt in the right pdf viewer and you'll see some helpful notes in red.

Evidence for ancient antibiotics

A chemist, a doctor, and two anthropologists walk into a bar. Mark Nelson, Andrew Dinardo, Jeffery Hochberg, and George Armelagos discovered that had they been Ancient Nubians, their beer would have contained antibiotics. This would have been nearly two thousand years before the "first" discovery of the antibiotic penicillin by Alexander Fleming which won him his Nobel Prize. Using acid extraction and mass spectroscopic characterization, they investigated reports on bones that when test with UV light produced yellow-green fluorophore deposition bands indicative of tetracycline. They rejected the claims that the exposure was postmortem and proposed the contents had been ingested over a long period of time. According to Nelson, this ancient population did not accidentally mass produce the antibiotic. It is believed that the nutrition and pharmacological effects of the fermentation was purposefully done.

Fleming's discovery of penicillin

Alexander Fleming is famous for, among other things, his discovery of penicillin. As the old tale goes, some of his bacterial cell culture plates became contaminated from the air, and he came to work the next morning to realize that a contaminating mould was secreting something which seemed to be killing the bacterial cells. He carried out a series of careful experiments characterizing the mould (determined to be of the genus Penicillium) and the effects of its secretion as an anti-bacterial agent. His initial article received little attention, and mass culturing the mold and extracting the penicillin itself was difficult. He gave up trying and the project was quickly picked up by Howard Florey and  Ernst Boris Chain. With funding from the US and UK in WWII, Florey and Chain were able to figure out how to produce mass quantities. Fleming, Florey, and Chain shared the Nobel Prize in 1945 for this discovery.

Natural selection changes allele frequencies

Researchers had known that marine sticklebacks which colonized freshwater, an event that had happened naturally multiple times, will gradually lose their bony armor plating. This was presumed to be due to an increase in fitness sans armor when living in a freshwater environment, but armor is been maintained in the marine environment due to a fitness advantage. The armor is controlled mainly by a single locus, Eda. The allele of Eda which causes decreased armor is ancient and is segregating at low frequency in the natural marine populations.

Barrett, Rogers, and Schluter trapped marine armored sticklebacks and transplanted them into freshwater ponds. They observed the expected loss of armor in the now-freshwater fish. They tracked allele frequencies at the Eda locus as well as phenotypes of the fish over time to determine if the loss of armor was the result of positive selection. The combination of natural founding populations, natural environments, and phenotype & allelic correlations makes this experiment a particularly simple and elegant example of modern evolutionary research.

Jellyfish enlighten our view of cells.

Fluorescent North American jellyfish species contain green fluorescent protein that absorbs blue light from the environment and in turn produce a green luminescence. Researchers became interested in this protein in particular, compared to other fluorescent methods, due to its ability to fold and function without the need for additional enzymes. The protein’s gene can be delivered into novel genomes using viruses or a number of other techniques to cause it to be expressed in certain cell types. This gives us the ability to follow cell lines as they develop and study gene expression, both of which were too small and difficult to identify before this development. This work resulted in a Nobel Prize in Chemistry in 2008 and has continued to be developed into a multitude of colors and inspired work and development of other proteins that emit near-infrared light that can be more easily detected through tissue.

Hawk moths use their genitals to jam bats’ sonar.

When we think of sonar jamming we picture a modern day military tactic, yet hawk moths have long been using the same strategy in order to also counteract the radar of their enemies as well. Bats rely on ultrasonic echolocation to see their surroundings and locate prey, hawk moths are able to recognize the bat’s sonar and respond by rubbing their genitals against their abdomens to create a responding ultrasound that is meant to startle or hinder the bat’s echolocation. Moths have a history of unique adaptation to counter predation by bats but the work by Barber showed that there are even differences within the same species between the sexes in what mechanism is used to get the same ultrasound effect. The ultrasound response by hawk moths is only used near the end of the bat attack sequence and could hint at it being a last line of defense among an arsenal of already existent antipredator adaptations.

The Miller Experiment: Lightning may have created the building blocks of life.

In 1952, Stanley Miller conducted an experiment to see if he could create organic compounds from inorganic compounds.  To do this he tried to create conditions similar to what earth might have been like before life emerged on a primitive Earth.  A mixture of water vapor, methane, ammonia, and hydrogen in the presence of electrical discharge (lightning) caused the water to turn red.  This color change was due to the presence of organic compounds.  The compounds generated by this method were ran on paper chromatogram and some were determined to be amino acids when compared to chromatograms of known compounds.  Following Miller's death, examination of sealed vials revealed that Miller actually generated many more amino acids than originally reported. 

Don’t go tanning at 4 in the morning (at least if you are mouse)

Even though the Nobel Chemistry Price committee rewarded Dr. Aziz Sancar for his DNA repair work, he is focusing in studying the circadian clock now. One of reason for this change is that genes involved in nucleotide excision repair genes (NER, a key pathway in DNA repair that he studied) have different expression levels throughout the day and are controlled by the cell’s circadian rhythms. In this paper, he shows that behavior for XPA, an important NER protein. In addition, he correlates its expression with the odds of mice getting skin cancer depending on the time they are exposed to UV light. Unfortunately, these results are hard to extrapolate to humans as we don’t have the same circadian clock as mice, so I can’t really tell you what time of the day is best to go sunbathe!